1. The Invention
This invention relates to methods of preparing prostaglandins and prostaglandin derivatives. In a further aspect, this invention relates to 13-cis prostaglandin derivatives and methods of making such derivatives. In a still further aspect, this invention relates to cis-octenol ether copper.sup.(I) lithium reagents and methods of preparing such reagents. In another further aspect, this invention relates to racemic octenol ether copper.sup.(I) lithium reagents and also optically active (R)- or (S)-octenol ether copper.sup.(I) lithium reagents. In still another aspect, this invention relates to methods of preparing cis prostaglandin derivatives, using such octenol ether copper.sup.(I) lithium reagents. This invention also relates to methods of preparing prostaglandins by the rearrangement of 13-cis prostaglandins to the corresponding 13-trans isomers.
2. The Prior Art
Prostaglandins are a group of chemically related 20-carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acids: ##STR1##
The prostaglandins having a hydroxy group at the C-11 position and a keto group at the C-9 position are known as the PGE series, those having a hydroxyl group in place of the keto group are known as the PGF series and are further designated by an .alpha. or .beta. suffix to indicate the configuration of the hydroxyl group at said position. The natural compounds are the 60-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5, C-13 and C-17, the unsaturation is also indicated by suffix. Thus, for example, PGE.sub.1 refers to a prostanoic acid having a trans olefin bond at the 13-position. For a review on prostaglandins and the definition of primary prostaglandins, see, for example, S. Bergstrom, Recent Progress in Hormone Research 22, pp. 153-175 (1966) and Science 157, page 382 (1967) by the same author.
Prostaglandins are widely distributed in mammalian tissues and have been isolated from natural sources in very small amounts. In addition a number of the natural occurring prostaglandins have been prepared by chemical synthesis; note, for example, J. Am. Chem. Soc. 91, 5675 (1969), J. Am. Chem. Soc. 92, 2586 (1970) and J. Am. Chem. Soc. 93, 1489-1493 (1971) and references cited therein, W. P. Schneider et al, J. Am. Chem. Soc. 90, 5895 (1968), U. Axen et al, Chem. Commun., 303 (1969), and W. P. Schneider, Chem. Commun. 304 (1969).
Because of the remarkable range of biological and pharmacological properties exhibited by this family of compounds, a great deal of interest has focused upon such compounds and accordingly we have discovered novel 13-cis prostaglandin derivatives and felicitous high yield processes and reagents for preparing such 13-cis prostaglandin derivatives and prostaglandins.